Derivatives of dihydro and tetrahydrofurans



DERIVATIVES OF DIHYDRO AND TETRAHYDROFURANS Werner Richard Boehme,Somerville, N.J., assignor to Ethicon, Inc., a corporation of New JerseyNo Drawing. Application August 27, 1958 Serial No. 757,451

11 Claims. (Cl. 260-297) wherein Z is an ethylene or vinylene radicalwhich, if desired, may be substituted by a carboxyl group, an alkylradical such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.,or an ether group, such as methoxy, ethoxy, propoxy, etc. Further, R inthe above structural formula is the group:

wherein Y is hydrogen or a saturated lower hydrocarbon, i.e. lower alkylsuch as methyl, ethyl, propyl, iso propyl, butyl, isobutyl, pentyl,isopentyl, hexyl, isohexyl, etc.; X is hydrogen or a lower hydrocarbonsuch as one of those defined hereinbefore; cycloalkyl, for examplecyclopentyl, cyclohexyl; monocyclic aryl, for example phenyl which, ifdesired, may be further substituted by alkyl or alkoxy groups;dialkylaminoalkyl, for example dimethylaminomethyl, dimethylaminoethyl,diethylaminomethyl, diethylaminoethyl, etc., a heterocyclic substituentcontaining oxygen, nitrogen or sulfur linkages, for example morpholyl,pyrrolidyl, piperidyl, pyridyl, thiazolyl, etc.; R and R are,interchangeably, lower alkoxy, for example methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, etc., and R is hydrogen, lower alkyl, forexample methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, etc.

The compounds of this invention are useful as intermediates.2-acetoacetyl-2,5-dimethoxy-2,S-dihydrofuran, for example, may beconverted to 2,3,6-trihydroxyacetophenone and2,2,4,4',5,5'-hexahydroxy-3,3'-diacetylbiphenyl as shown in Example IIIbelow. Further, 2- acetoacetyl-Z,S-dimethoxytetrahydrofuran may beconverted to 2,3-dihydroxyacetophenone as shown in Example IV below.These and other polyhydroxyphenylketones, whose preparation from thenovel compounds of this invention will be obvious to those skilled inthe art, are known. They find application in the chemical and relatedindustries, as tanning agents, as constituents (along with ferroussalts, i.e. sulfates, etc.) in permanent inks, and as photographicdevelopers. Their usefulness as tanning agents stems from their abilityto complex with proteins, e.g. collagen, to form products which are moredurable and more resistant to enzymatic digestion than the proteinsthemselves. Further, the compounds Patented Jan. 12, 1960 of thisinvention, by virtue of the diketo group in the 2-position are useful aschelating agents, being capable of forming chelates with such metals aslead, uranium, cobalt, iron, nickel, etc. Because of their ability toabsorb ultraviolet light in the range from 280 to 300 millimicrons, thenovel compounds are also useful as ingredients in sun screencompositions. For this purpose they may be incorporated iuto suitablecarriers such as hydrophilic ointment bases (e.g. Hydrophilic Ointment,U.S.P. XV) or lotions in quantities ranging from 2% to 10% in accordancewith methods well known to those skilled in the art. I

The novel'eompounds of this invention may be prepared by condensing anappropriately substituted furoic acid ester with a monoketone ormonoketo derivative containing at least one alpha hydrogen atom, forexample acetone, acetophenone, 4-diethylamino-2-pentanone,cyclohexanone, acetylthiophene, cyclopentylacetone, phenylacetonc, etc.in the presence of a strong basic catalyst. The condensation ispreferably conducted in the presence of a suitable organic solvent suchas an ethereal solvent; for example dioxane, diethyl ether,tetrahydrofuran; a hydrocarbon such as hexane, benzene or toluene, or analkanol such as methanol or ethanol.

As catalysts there may be used any one of a variety of strong bases suchas the alkali metal hydrides; for example sodium or potassium hydride;alkali metal alkoxides, for example sodium ethoxide or potassiumt-butoxide; metallic sodium, alkali metal amides, such as sodamide orpotassium amide; triphenyl methyl sodium; mesitylmagnesium bromide, etc.

The reaction may be carried out over a wide temperature range, dependingupon the nature of the reactants undergoing condensation and thevolatility of the solvents employed; for example, from about 0 C. toabout 125 C. In most cases a range from about 30 C. to about C. isadequate.

If desired, the novel dihydrofurans of this invention may be convertedto the corresponding tetrahydrofurans by catalytic hydrogenation, thatis to say, with hydrogen in the presence of a catalyst selected from themetals of the eighth group of the periodic system, such as'nickel, forexample Raney nickel; palladium, platinum or rhodium. They may beemployed on carriers such as barium carbonate or charcoal, in the formof special preparations such as palladium black, or preferably, asoxides such as platinum oxide. The reduction is most advantageouslycarried out in the presence of a solvent such as a lower alkanol, forexample methanol or ethanol and, if so desired, under pressure.

Yet another convenient method for preparing the novel tetrahydrofuransof this invention is by hydrogenation of the appropriately substituteddihydrofuroic acid ester, followed by Claisen condensation to thedesired diketone. The hydrogenation and subsequent conversion to thediketone may be carried out in accordance with the methods describedhereinabove.

The following examples are illustrative of the invention, but are not tobe construed as limitative thereon.

Example I A solution of 38.0 parts by weight of ethyl furoate and onepart by volume of concentrated sulfuric acid in 250 parts by volume ofmethanol is electrolyzed in a nickel cathode-graphite anode cell asdescribed by Clauson-Kaas, Limborg and Glens, Acta. Chem. Scand. 6, 531(1952). 19.4 ampere hours are passed in 8 hours beginning at 9 volts and3.5 amperes at -15 to -22 C. The solution is then neutralized with asolution of sodium methoxide in methanol and concentrated under reducedpressure. The precipitated sodium sulfate is latcd as in the foregoingexample.

filtered oil and the filtrates distilled. The product, ethyl2,5-dimethoxy-2,5-dihydrofuroate, boils at 136139 C./ 21 mm., 11 1.4480.

A mixture of 25.9 parts by 'weight of ethyl2,5-dimethoxy-2,S-dihydrofuroate, 6.8 parts by weight of so.- diumhydride and 6 glass marbles is stirred slowly in' a 3-neck 500 ml.round-bottom flask. A solution of 16.5 parts by weight of acetone in 25parts by volume of anhydrous ether is added dropwise during a periodof ahalf hour, maintaining the temperature at 30-40 C. with occasionalcooling. Hydrogen is evolved and a thick amber paste results. Stirringis continued for a half hour longer, 100 parts by volume of anhydrousether is added and themixture is allowed to stand at room temperaturefor three days. Fifteen parts by volume of 95% ethanol is added, themixture is cooled to C., and the complex decomposed with 100 parts byvolume of waterand 18 parts by Weight of acetic acid. The layers areseparated and the aqueous phase is extracted with 50 parts by volume ofether. The combined ether solutions are washed with sodium bicarbonatesolution and dried over anhydrous magnesium sulfate. Distillation of theether solution gives a light yellow liquid,2-acetoa'cetyl-2,5-dimethoxy-2,5-dihydrofuran, boiling at 97 C./0.2 mm.,a 1.4956.

Example II A mixture of 26.1 parts by weight of methyl2,5-dimethoxytretrahydrofuroate [prepared by the method of Clauson-Kaasand Limborg, Acta. Chem. Schand. 6, 551 (1952)], 6.6 parts by weight ofsodium hydride and 6 glassmarbles is treated with 16 parts by weight ofacetone in 25 parts by volume of anhydrous ether, and the product,2-acetoacetyl-2,5-dimethoxytetrahydrofuran, is iso- It is obtained as apale yellow liquid boiling at 8791 C./ 0.5 mm., n 1.4825. i

, Example 111 A mixture of 5.35 parts by weight of 2-acetoacetyl-2,5-dimethoxy-2,5-dihydrofuran, 50 parts by volume of 0.1 N hydrochloricacid and a small chip of Dry Ice is stirred for six hours in a closedflask. 2,2,4,4,5,5'-hexahydroxy-3,3'-diacetylbipheny1 separates as amustard-yellow precipitate and is removed by filtration of thesuspension. It melts at 280 C. (dec.). V

The clear yellow filtrates are cooled in ice.2,3,6-trihydroxy-acetophenone separates as brilliant yellow crystalswhich are purified by recrystallization from water or by sublimationunder reduced pressure. The melting point is 157.5l59 C.

Example I A mixture of 7.4 parts by weight of 2-acetoacetyl-2,5-dimethoxytetrahydrofuran and 75 parts by volume of 0.1 N hydrochloricacid is refluxed for one hour with stirring and cooled. The yellowcrystalline product, 2,3-dihydroxyacetophenone, which separates, isremoved by filtration. It melts at 9898.5 C. when recrystallized frombenzene-hexane.

bicarbonate, a yellowprecipitate of 3-nic0tinoylcatechol separates. Itmelts at 154156 C. when recrystallized from heptane.

Example VI A solution of 38.0 parts by weight of ethyl furoate and 250parts by volume of absolute ethanol containing one part by volume ofconcentrated sulfuric acid is electrolyzed and the ethyl2,5-diethoxy-2,S-dihydrofuroate (31.6 parts by weight, boiling point145-150 C./21 mm.) is isolated as in Example I. The product is condensedwith 16.5 parts by weight of acetone and 6.8 parts by weight of sodiumhydride as in Example I, giving Z-acetoacetyl-2,5-diethoxy-2,5-dihydrofuran. Upon hydrolysis (as in Example III) itgives 2,3,6-trihydroxyacetophenone, melting point 158-159 C.

Example VII A mixture of 38.0 parts by weight of methyl 2,5-din1ethoxytetrahydrofuroate, 4.8 parts by weight of sodium hydride and25.8 parts by weight of diethylaminoacetone [prepared by the method ofM'agee and Henze, J.A.C.S. 60, 2148 (1938)], is condensed as in ExampleI. The dried ether extracts upon evaporation at 50 C./0.l mm. leaves aviscous residue of 2-diethylaminoacetoacetyl-2,5-dimethoxytetrahydrofuroate.

Example VIII Example IX A mixture of 31.6 parts by weight of methyl2,5-dimethoxy-S-isopropyltetrahydrofuroatev [prepared according toNedenskov et al., Acta. Chem. Scand. 9, 17 (1955)], 6.8 parts by weightof sodium hydride and 16.5 parts by weight of acetone is condensed as inExample'I to give 2-acetoacetyl-5-isopropyl-2,5-dimethoxytetrahydrofuranboiling at 93-97" C.'/0.l mm.

Example X A mixture of 25.9 parts by weight of methyl2,5-dimethoxytetrahydrofuroate, 6.8 parts by weight of sodium hydrideand 28.5 parts by weight of pinacolone is condensed as in Example I. Theresulting 2-pivaloylacetyl-2,5-dimethoxytetrahydrofuran boils at ll2C./O.l vmm. l V I Example XI A mixture of 25.9 parts by weight of methyl2,5-dimethoxytetrahydrofuroate, 6.8 parts by weight of sodium hydrideand.45.0 parts by weight of 4-rnethylpropiophenon [prepared according toNoller and Adams, J.A.C.S. 46, 1889 (1924) is condensed as in'ExarnpleI. Distillation of the dried ether solution at C./0.l mm. leaves aliquid residue of 2-[a(4-methylbenzoyl)-propionyl]-2,5-dimethoxytetrahydrofuran. p

Example X II' A mixture of 38.0 parts by weight of methyl2,5-dimethoxytetrahydrofuroate, 4.8 parts by weight of sodium hydrideand 24 parts by weight of acetophenone is condensed as in Example I.Distillation of the dried ether solution on the steam bath at 0.1 mm.leaves a viscous residue of 2-benzoylacetyl-2,5-dimethoxytetrahydrofuran which is hydrolyzed by the proceduredescribed in Example IV to 2,3-dihydroxybenzophenone, melting point 65C.

Example XIII Percent 2-acetoacetyl-2,5-dimethoxy-2,S-dihydrofuran 9.0Glycerin 3.0 Borax 2.0 Alcohol 15.0 Water 70.5 Perfume 0.5

6 8. The new compound 2-pivaloylacetyl-2,5-dimethoxytetrahydrofuran.

9. The new compound2-[a-(4-methylbenzoyl)-propionyl]-2,S-dirnethoxytetrahydrofuran.

10. The new compound Z-benzoylacetyl-Z,S-dimethoXytetrahydrofuran.

11. A compound of the general formula:

R4\ z R, o 0 R \O/ R1 wherein Z is a member of the group consisting ofethylene, vinylene, lower alkyl ethylene, lower alkoxy ethylene, loweralkyl vinylene and lower alkoxy vinylene; R is the radical --COGHCOXwherein Y is a member of the group consisting of hydrogen and loweralkyl; and X is a member of the group consisting of hydrogen, loweralkyl, cycloalkyl containing 5 to 6 carbon atoms, phenyl, lower alkylphenyl, pyridyl and lower dialkylaminoalkyl; R and R are lower alkoxy;and R is a member of the group consisting of hydrogen and lower alkyl.

No references cited.

11. A COMPOUND OF THE GENERAL FORMULA: